Somatic stem cells are undifferentiated cells that can renew themselves and can also differentiate to specialized cell types of a tissue or organ, such as neural stem cells and hematopoietic stem cells. While stem cells derived from an early embryo, known as embryonic stem cells (ESCs), can be maintained in culture for an extended period without losing their differentiation potential (Thomson et al., Science, 1998, 282: 1145-1147; Evans & Kaufamn, Nature, 1981, 5819: 154-156), somatic stem cells like brain (neural) or blood stem cells gradually lose their differentiation potentials when cultured for a long period of time. A brain stem cell can generate all types of cells in the brain and spinal cord but after expansion it can only generate neural cells of a particular brain region or even particular cell types of a brain region (Temple, Nat. Rev. Neurosci., 2001, 2: 513-520; Gage, Science, 2000, 287: 1433-1438).
Maintenance of ESCs depends on the transcription network orchestrated by stem cell (pluripotent) transcription factors including Oct4, Nanog, and Sox2. These transcription factors block developmental genes while activating stem cell genes, thus inhibiting differentiation and maintaining the stem cell state (Boyer et al., Cell, 2005, 122: 947-956). Activation of this stem cell transcription network reprograms somatic (e.g. skin) cells to stem cells, also known as induced pluripotent stem cells (iPSCs) (Yu et al., Science, 2007, 318: 1917-1920; Takahashi et al., Cell, 2007, 131: 861-872).
Transplantation of hESC-differentiated neural derivatives often ends up with over-growth of the grafts (Roy et al., Nat. Med, 2006, 12: 1259-1268; Sonntag et al., Stem Cells, 2007, 25: 411-418). hESC derived neurons and glia are a desirable source of cells for replacement therapy. However, transplantation of stem cell derived neural cells for therapeutic purposes is often confounded by the tumorigenic potential of undifferentiated neuroepithelial cells.
Needed in the art is a method of maintaining primate somatic stem cells, such as brain stem cells, in culture without losing differentiation potential. Like the generation of iPSCs by pluripotent transcription factors, transcription factor(s) critical for maintaining neural stem cells would need to be identified and regulated. Also needed in the art is a method of decreasing the possibility of tumor formation in a transplant.